PROJECT SUMMARY Ovarian cancer continues to have the highest case-fatality ratio of any gynecologic cancer. One of the foremost barriers in the field of ovarian cancer therapeutic research is the failures of currently-established therapies to increase initial cure rates; particularly in cases of drug resistant tumors. Tumor hypoxia has been known to negatively affect chemotherapy outcomes for decades, as it can inhibit tumor cell proliferation and induce cell cycle arrest - ultimately conferring chemoresistance as anticancer drugs preferentially target rapidly-proliferating tumor cells. Attempts at overcoming hypoxia-mediated drug resistance by combining various chemotherapeutic agents has not been successful, and results in increasing the harmful effects already toxic therapies. This leads to debilitating side effects, including hematologic, neuropathic, renal and gastrointestinal toxicity which significantly diminish the quality of life of patients. STAT3 over-expression has been associated with both hypoxia and chemotherapeutic resistance in multiple tumor types. The overarching goal of this proposal is to further elucidate mechanisms of STAT3 activation in ovarian cancer, and determine how this contributes to the development of drug resistance. Additionally, we have developed a novel class of dual-function compounds based on a diarylidenyl piperidone (DAP) backbone conjugated to an N- hydroxypyrroline (NOH; a nitroxide precursor) group that have potent antineoplastic activity against ovarian cancer cells while imparting antioxidant protection to noncancerous tissues. The activity of DAP compounds is mediated by inhibition of STAT3 signal transduction. Given this DAP compounds may overcome both the problem of hypoxia related drug resistance and increased toxicity. This will be evaluated using an in vivo orthotopic ovarian cancer model. This study will advance the understanding of the fundamental mechanisms of ovarian tumorigenesis, and apply this knowledge to improve the treatment of ovarian cancer patients who develop hypoxia-mediated chemotherapy resistance. This could pave the way for clinical investigation of DAP compounds as adjuncts to current therapeutic regimens for ovarian cancer.